In the last few years, metallodrugs play a key role in the development of medicinal chemistry. The choice of metal ion, its oxidation state and stability, and the choice of inert and labile ligands ...are just some of the very important facts which must be considered before starting the synthesis of complexes with utilization in medicinal purpose. As a result, a lot of compounds of different transition metal ions found application for diagnostic and therapeutic purpose. Beside all, gold compounds have attracted particular attention. It is well-known that gold compounds could be used for the treatment of cancer, HIV, rheumatoid arthritis (chrysotherapy), and other diseases. This metal ion has unoccupied d-sublevels and possibility to form compounds with different oxidation states, from −1 to +5. However, gold(I) and gold(III) complexes are dominant in chemistry and medicine. Especially, gold(III) complexes are of great interest due to their structural similarity with cisplatin. Accordingly, this review summarizes the chemistry of some mononuclear and polynuclear gold(III) complexes. Special attention is given to gold(III) complexes with nitrogen-donor inert ligands (aliphatic or aromatic that have a possibility to stabilize complex) and their kinetic behavior toward different biologically relevant nucleophiles, mechanism of interaction with DNA/bovine serum albumin (BSA), cytotoxic activity, as well as computational calculations.
The pioneer in clarification of the substitution reactions between platinum(II), palladium(II) and gold(III) complexes with biomolecules such as guanosine-5'-monophosphate (5'-GMP), glutathione (GSH) ...and L-methionine (L-Met) was Professor Dr. Živadin D. Bugarčić and his research group. In this minireview we highlight the important results of his research in the field of studying mechanisms of the substitution reactions of various transition metal complexes with square-planar geometry. Knowledge of the kinetic coordination chemistry of these transition metal ions helps to clarify the mechanism of action of metallodrugs for development of complexes with potent antitumor activity. The results are presented comparatively to aid in the future development of novel antitumor agents with unique mechanisms of action.
Four new complexes of Pt(II) and Pd(II), Pd(L1)ClCl
1
, Pd(L2)ClCl
2
, Pt(L1)ClCl
3
and Pt(L2)ClCl
4
(where L1 = 2,6-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine and L2 = ...2,6-bis(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine), were synthesized. Characterization of the complexes was performed using elemental analysis, IR,
1
H NMR spectroscopy and MALDI-TOF mass spectrometry. The substitution reactions of
1–4
complexes with
l
-methionine (
l
-met),
l
-cysteine (
l
-cys) and guanosine-5ʹ-monophosphate (5ʹ-GMP), were studied spectrophotometrically at physiological conditions. Complexes with ligand L1 (
1
or
3
) were more reactive than those with ligand L2 (
2
or
4
) by a factor ranging up to 1.57 and 3.71, respectively. The order of reactivity of the nucleophiles was:
l
-met >
l
-cys > 5ʹ-GMP. The interactions of complexes with calf thymus-DNA (CT-DNA) and human serum albumin (HSA) were studied by Uv–Vis absorption and fluorescence emission spectroscopy. Competitive binding studies with intercalative agent ethidium bromide (EB) and minor groove binder Hoechst 33258 were performed as well. All studied complexes can interact with DNA through the intercalation and minor groove binding, where the latter was preferred. The binding constants (10
3
and 10
4
M
−1
) for the interaction of complexes with HSA indicate the moderate binding affinity of complexes
1–4
to protein. The trends in the experimental results of binding studies between complexes
3
and
4
with DNA and HSA were compared to those obtained from the molecular docking study. Biological evaluation of cytotoxicity of
1
and
2
on HCT-116 and MDA-MB-231 cell lines showed significant cytotoxic and prooxidative character, while
2
also exerted extraordinary selectivity towards colon cancer in comparison to breast cancer cells.
Graphic abstract
The nucleophilic substitution reactions, DNA/HSA interactions, molecular docking and biological activity of bis(triazinyl)pyridine complexes of Pt(II) and Pd(II) were studied.
Newly palladium(II) complexes (C1, C2) with derivatives of 2-aminothiazoles (L1 = 2-amino-6-methylbenzothiazole, L2 = 2-amino-6-chlorobenzothiazole), general formula PdL2Cl2 were synthesized and ...characterized by elemental microanalyses, IR, NMR spectroscopy and X-ray spectroscopy in case of Pd(L2)2Cl2. The kinetic of the substitution reactions of complexes and the nucleophiles, such as guanosine-5′-monophosphate (5’-GMP), tripeptide glutathione (GSH) and amino acid L-methionine (L-Met), were studied by stopped-flow technique. The complex C2 was always more reactive, while the order of the reactivity of the nucleophiles, due to the associative mode of the reaction, was L-Met > GSH > 5’-GMP. In order to determine the type of interactions between palladium(II) complexes and calf thymus DNA (CT-DNA), we used electronic absorption spectroscopy, viscosity measurements, and fluorescence spectroscopic studies, while interactions with bovine serum albumin (BSA) were determined only with fluorescence spectroscopic studies. The observed results confirmed that both complexes bound to DNA by groove binding. The significantly strong interaction with BSA, especially for complex C2, was also observed. In vitro cytotoxic activity was evaluated against four tumor cell lines, 4 T1, CT26, MDA-MB-468, HCT116 and mesenchymal stem cells (mMSC). C1 complex showed higher cytotoxic activity against CT26 cell line. Flow cytometry analysis showed that C1 stimulated apoptosis of tumor cells via inhibition of expression of antiapoptotic Bcl-2 molecule and decelerated proliferation by decreasing Cyclin-D and increasing expression of P21. In vitro antimicrobial activity for ligands and corresponding palladium(II) complexes was investigated by microdilution method and minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) were determined. Tested compounds exhibited selective and moderate activity.
Newly complexes PdL2Cl2 (L1 = 2-amino-6-methylbenzothiazole, L2 = 2-amino-6-chlorobenzothiazole) were synthesized and characterized by elemental microanalysis, IR, 1H, 13C NMR and X-ray spectroscopy for Pd(L2)2Cl2. The kinetic of the substitution reactions and interactions of complexes with calf thymus DNA and bovine serum albumin were determined. In vitro cytotoxic and antimicrobial activity were tested. Display omitted
•Two new palladium(II) complexes were synthesized.•Characterization was performed by IR, 1H and 13C NMR and X-ray spectroscopy.•The kinetic of the substitution reactions were studied by stopped-flow technique.•The interactions of new complexes with calf thymus DNA and bovine serum albumin were investigated.•Cytotoxic and antimicrobial activities of palladium(II) complexes were evaluated.
The kinetics of the substitution reactions between bifunctional Au(III) complexes, AuCl
2
(bipy)
+
, AuCl
2
(dach)
+
and AuCl
2
(en)
+
(bipy = 2,2″-bipyridine, dach = (1 ...R,2R)-1,2-diaminocyclohexane, en = ethylenediamine), with biologically relevant ligands such as glutathione (GSH), L-methionine (L-Met) and L-cysteine (L-Cys) is determined. All kinetic studies are performed in 25 mM Hepes buffer (pH = 7.2) in the presence of NaCl (25 mM) to prevent hydrolysis of the complexes. The reactions were followed under pseudo-first-order conditions using stopped-flow UV-Vis spectrophotometry at determined working wavelengths at three different temperatures (288.2, 298.1, and 309.8 K). DFT theoretical approach was applied to calculate thermodynamic and kinetic parameters that determined an operative mechanism of substitution reactions for all complexes and L-Cys as a selected model substituent. The obtained kinetic data showed that all complexes have similar reactivity; AuCl
2
(bipy)
+
is the most reactive while AuCl
2
(en)
+
is the least reactive. The second step of the substitution reaction is much faster than the first. The reactivity of the studied nucleophiles decreases in order L-Met > L-Cys > GSH. According to the values of the activation parameters determined experimentally and theoretically, all substitutions follow an associative model.
Abstract
Occupational exposure in Bosnia and Herzegovina is regulated by the national regulation on radiation protection for occupational and public exposure. All radiation workers are required to be ...monitored using whole body passive thermoluminescent dosemeters and, in case of non-uniform external exposures, by dosemeters that would indicate dose to the most affected body parts. Exposed workers are almost exclusively employed in the medical field, and some of them work in nuclear medicine departments where they handle unsealed radioactive sources. Introduction of the positron emission tomography–computed tomography (PET–CT) in two largest clinical centers in the country was expected to cause the increase of equivalent doses to hands received by staff handling the positron emitting radionuclides. Hence, routine monitoring of finger doses became a necessity. The purpose of this study was to evaluate the available data on monitoring with ring dosemeters during PET–CT procedure in two hospitals in Bosnia and Herzegovina and compare them with other practices in the nuclear medicine department, as well as with the results of monitoring in other countries. In general, results confirm that effective doses, as well as equivalent doses to hands, are well below annual dose limits. Finger dosemeters have been proven to be an invaluable asset in the incidental situations that sometimes occur in nuclear medicine departments. Different number of patients and differences in injection methodologies are identified as a possible source of differences between doses in two hospitals. Overall, routine evaluation of doses to hands provides a sound basis for possible optimization processes, as well as confirmation of good practices.
A brief overview of mechanistic studies on the reactions of different Pt(
ii
) complexes with nitrogen- and sulfur-donor biomolecules is presented. The first part describes the results obtained for ...substitution reactions of mono-functional Pt(
ii
) complexes with different biomolecules, under various experimental conditions (temperature, pH and ionic strength). In addition, an overview of the results obtained for the substitution reactions of bi-functional Pt(
ii
) complexes, analogous to cisplatin, with biomolecules is given. The last part of this report deals with different polynuclear Pt(
ii
) complexes and their substitution behaviour with different biomolecules. The purpose of this perspective is to improve the understanding of the mechanism of action of Pt(
ii
) complexes as potential anti-tumour drugs in the human body.
The mechanistic behaviour of different mono- and bifunctional as well as mono- and dinuclear Pt(
ii
) complexes is reviewed in reference to their substitution reactions with biologically relevant nucleophiles.
Mechanistic insight gained on the chemistry of different mononuclear Pt(II) and Pt(IV), as well as di-nuclear Pt(II) complexes, the tuning of their lability through steric and electronic (σ-donor and ...π-acceptor) effects, their interaction with sulfur- and nitrogen-donor bio-relevant nucleophiles, the elucidation of structure-reactivity relationships, and DFT calculations on ground, transition and product state complexes, are reported.
Display omitted
•Mechanistic studies on different mononuclear, mono- and bi-functional Pt(II) complexes.•Mechanistic studies on different mononuclear Pt(IV) complexes.•Mechanistic studies on different di-nuclear Pt(II) complexes.•Structure-reactivity relationships for mono- and di-nuclear Pt(II) and Pt(IV) complexes.
This personal account reports on the mechanistic insight gained on the chemistry of potential Pt antitumor agents based on the collaborative research between the groups of Živadin Bugarčić in Kragujevac (Serbia) and Rudi van Eldik in Erlangen (Germany). The work focuses on different mononuclear Pt(II) and Pt(IV), as well as dinuclear Pt(II) complexes, the tuning of their lability through steric and electronic (σ-donor and π-acceptor) effects, their interaction with sulfur- and nitrogen-donor bio-relevant nucleophiles, the elucidation of structure-reactivity relationships, and DFT calculations on ground, transition and product state complexes. It presents an overview of the investigated systems and reveals mechanistic information on the basis of spectroscopic and kinetic measurements.
In this paper, we investigated water exchange reactions and substitution of aqua RuII complexes of general formula Ru(terpy)(N^N)(H2O)2+ (where N^N = ethylenediamine (en), 1,2‐(aminomethyl)pyridine ...(ampy) and 2,2′‐bipyridine (bipy)) by ammonia and thioformaldehyde. These reactions were studied in detail by applying conceptual density functional theory. This approach enabled us to gain further insight into the underlying reaction mechanism at the microscopic level (involving only direct participants of the reaction, without the influence of the solvent) and to put the concept of reaction mechanism on a quantitative basis. The course of the chemical reaction along the reaction coordinate ξ, is rationalized in terms of reaction energy, force, dipole moment, and reaction electronic flux (REF). The results yield and characterize the significant influence of an intermolecular hydrogen bond formed between the entering and the spectator ligand to the overall energy barrier of the reactions.
Conceptual DFT calculations can be a powerful tool in providing a better understanding of the reaction mechanism at the microscopic level, without the interference of the solvent molecules. Throughout this paper these kind of calculations were used to investigate water substitution reactions on RuII‐aqua complexes. The results yield and characterize the significant influence of an intermolecular hydrogen bond formed between the entering and the spectator ligand to the overall energy barrier of the reactions.
The first synthesis of racemic 2‐(aminomethyl)cyclopropane‐1,1‐dicarboxylic acid was developed involving sequential iodocarbocyclization, azidation, saponification and reduction of dimethyl ...2‐allylmalonate. The developed synthetic pathway avoids reactions such as ring opening of the cyclopropane ring toward acyclic δ‐amino carboxylic acid derivatives or lactamisation toward bicyclic methyl 3‐aza‐2‐oxobicyclo3.1.0hexane‐1‐carboxylates which occur in alternative synthetic strategies.
A first synthesis of 2‐(aminomethyl)cyclopropane‐1,1‐dicarboxylic acid from dimethyl allylmalonate is developed through iodocarbocyclization, azidation, saponification and reduction, which bypasses the formation of 3‐aza‐2‐oxobicyclo3.1.0hexane‐1‐carboxylic acid derivatives.
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